Systematic review of renal denervation for the management of cardiac arrhythmias

Cardiac arrhythmias contribute significantly to morbidity and mortality worldwide [1, 2]. Atrial arrhythmias are the commonest arrhythmias observed in clinical practice with an increasing prevalence due partly to an ageing population, with atrial fibrillation (AF) alone affecting 33.5 million people globally [1]. AF is additionally linked with strokes which can be highly debilitating [3, 4]. By contrast, ventricular arrhythmias are less common but are associated with sudden cardiac death [5], affecting around 184,000–450,000 individuals per year in the United States of America [2, 6, 7].

Arrhythmias are complex biophysical phenomena, and despite significant advances in medical technology over the past decades, current medical and invasive management options cannot abolish their occurrences completely. Renal sympathetic denervation (RSD) was first performed in 1925 [8], but due to its inability to reduce blood pressure safely as well as effectively in patients with resistant hypertension, did not gain significant attention until the recent consequential findings of the HTN-1 [9] and HTN-2 [10] trials. Given that hypertension is one of the most important risk factors for developing AF and its recurrence [11], there has been speculation that RSD may reduce AF burden [12, 13]. Whilst this may be a direct consequence of BP reduction, there is some evidence that the impact of RSD on cardiac arrhythmias may be independent of BP effects [14]. RSD has also proven to have a role in several related conditions in which the autonomic nervous system plays an important role, such as heart failure, chronic kidney disease (CKD) and glucose metabolism [8, 15]. Thus, RSD empirically has a plausible biological mechanism to affect the autonomic nervous system, feedback onto the cardiovascular system, and together with early studies [14] hinting at a possible antiarrhythmic effect. Thus, the results of HTN-3 trial [16] that found that both the RSD and control groups showed similar BP reductions at 6 months, do not directly affect the potential of RSD in treating cardiac arrhythmias. The data from the HTN-3 [16] trial have been reported to be controversial for the following reasons: (1) medication adherence (2) suboptimal procedure performance, (3) patient selection and (4) operator experience [17‐19]. Since then, there have been many studies such as the DENERHTN trial [20], the SPYRAL HTN-OFF MED trial [21], RADIANCE-HTN SOLO trial [22] and SPYRAL HTN-ON MED [23] trial that report a significant reduction in BP.

In 2016, a systematic review examined the effects of RSD on cardiac arrhythmias [14]. However, since then, additional trials have been completed and published. Moreover, the review did not examine all domains relevant to RSD and cardiac arrhythmias. For example, whilst there is a relatively larger body of evidence on the short- and long-term effects of RSD on patients with AF and hypertension, the effects of RSD on AF in normotensive patients or on ventricular arrhythmias have yet to be fully investigated. In this study, we aim to perform an updated and comprehensive systematic review on the effects of RSD on both atrial and ventricular arrhythmias.

The role of RSD in attenuating cardiac arrhythmias lies in the link between the renal afferent and efferent sympathetic nervous system (SNS) fibres that modulate the central nervous system control of cardiac electrophysiological properties. The SNS increases HR and increases atrioventricular conduction which is potentially arrhythmogenic. RSD operates by dampening pathological SNS overstimulation. Moreover, the SNS innervates the kidneys, playing a major role in the pathophysiology of resistant hypertension via the renin–angiotensin–aldosterone system (RAAS) and sodium absorption. This supports the findings of recent studies that suggest this autonomic overdrive plays an important aetiological role in many cardiac arrhythmias such as AF and potentially an explanation of why it often coexists with hypertension. Recent evidence suggests that an overdrive of the SNS contributes to the “perception” of paroxysmal symptomatic AF episodes and hence it is promulgated that the dampening of SNS activity not only decreases BP but also may decrease the occurrence of such “perceived” arrhythmias particularly paroxysmal AF [43, 44]. Given that the autonomic nervous system innervates both atria and ventricles, it is postulated that RSD might have a role in treating arrhythmias of both atrial (i.e. AF) and ventricular origin (i.e. VT or VF) [45].

Hypertension has been shown to be the most relevant risk factor in the development of AF, which is itself the most common type of arrhythmia in the United Kingdom and set to grow in prevalence as the population ages [46, 47]. The link between the SNS activity, cardiac arrhythmias and hypertension is well documented and has been a target of interest for much research for numerous pharmacological and non-pharmacological interventions [48, 49]. Furthermore, first-line pharmacological treatments for hypertension such as angiotensin-converting enzyme (ACEi) inhibitors and angiotensin receptor blockers (ARBs) are also noted for their use in patients suffering from AF [48]. However, poor drug adherence [50] as well has the increased prevalence of treatment-resistant hypertension, a single intervention with long-term efficacy is seen as an increasingly attractive option for healthcare providers, researchers and patients. RSD has a controversial history regarding its use to lower BP of patients due to the findings of the SYMPLICITY HTN-3 trial [16]. However, redesigned so called ‘second generation’ studies such as SPYRAL HTN -ON, SPYRAL HTN-ON and RADIANCE SOLO have reported that RSD has been shown to reduce Office and Ambulatory BP in patients for up to 12 months [51]. However, though RSD has been shown to be effective in the short term (up to 12 months), there is still a paucity of data on the long-term outcomes of hypertensive patients. The largest study on the longer term outcome is the is the Global Simplicity Registry (GSR) a multi-centre study, which has reported data on more than 2500 patients up to 3 years post-procedure [52].

These extensive studies have, however, shown that RSD is a safe procedure for patients with no significant complications with sham or control groups. The majority of the studies in this systematic review had no complications. There was no mortality directly attributable to the procedure itself in any of the studies. Of note is the large variation in reporting of complications between the studies—the majority of complications were reported in two studies Steinberg et al. [30] and Ukena et al. [42]. The majority of complications were, however, benign with vasovagal effects being predominant. Only one arrhythmic complication (severe bradycardia) was seen, underlining the link between the SNS and cardiac electrophysiology.

Another safety concern surrounding RSD is the potentially deleterious effects on renal function. However, the safety of renal denervation has been shown in multiple studies such as Hering et al. [53] and Prasad et al. [54] where both found no significant alterations in renal function in patients with stage 3–4 kidney disease after renal denervation up to 12 and 24 months, respectively. Furthermore, with RSD, there was no significant difference in mortality or adverse outcomes in the studies that could be attributed to ventricular arrhythmias or the renal denervation procedure itself.

Quality of life scores, though initially may seem disappointing, likely do not reflect an accurate representation of the efficacy RSD on quality of life for cardiac rhythm disturbances—many of the trials were primarily driven for HTN and not for cardiac rhythm disturbances. The pre-existent rhythm disturbances may not be significantly impacting upon the baseline QoL making improvements hard to detect. HTN itself is largely asymptomatic, and therefore, QoL improvements are likely to be driven by reduced medication needs and contact with medical services in the studies where this was the primary end point.

The RSD procedure itself was technically more comparable. Similar radiofrequency energy use across the studies helps in comparison. Anticoagulation peri-procedurally was also largely with unfractionated heparin. However, ablation time was more variable (only one study used ablation < 30 s, all others > 60 s, though a significant number > 120 s). Thus, from a technical aspect, the largest point of difference is the ablation time (and therefore, total energy delivered) as well as the equipment used to deliver the energy. Ablation time may simply reflect operator familiarity with the anatomy to faithfully deliver the ablation to the target.

The effect of RSD on arrhythmic outcomes seems to be more pronounced. The atrial arrhythmia of primary concern in the studies was AF, with a secondary focus on atrial flutter. Flutter outcomes were not commented on between the two arms apart form in one study where there was a significant decrease in recurrence of atrial flutter. This is not unexpected as of the eight studies that measured outcomes RSD with concurrent ablation for AF/flutter, and all the protocols included empirical cavo-tricuspid isthmus line ablation if the patient had a history of atrial flutter, a procedure with a high success rate without adjunctive therapy. Therefore, it would not be expected to see significant recurrence, and therefore, reduction in recurrence of flutter regardless if RSD had been performed or not.

The outcomes for AF are worth considering carefully. Six studies measured pulmonary vein isolation (PVI) and compared it to PVI and RSD for the treatment of AF. The majority of these studies were in patients with a history of paroxysmal AF, a patient population in which PVI has greater success. However, two studies included patients with episodes of persistent AF as well as paroxysmal AF. Permanent AF was excluded, as by definition, these patients are not to be restored to sinus rhythm. In all the studies, there was a significant improvement in freedom from AF with adjunctive RSD treatment with PVI. Furthermore, the detection of AF was usually done with Holter monitoring, though at least half the studies used implantable devices to continuously monitor cardiac rhythms, which will improve detection rates of arrhythmias dramatically. The remaining four studies used Holter monitoring varying in duration from 24 h at prespecified times up to the 12-month follow-up period to 7 day Holter monitoring. In all these studies, there was statistically significant improvement in freedom from AF. The improvement in outcomes was consistent despite large variation in the ability to detect arrhythmias (i.e. the total time where surveillance for AF was conducted was variable between studies) suggesting a real effect rather than one driven by poor detection.

A plurality of studies documented similar improvements in PACs (premature atrial complexes) though this was not universal. Improvements in the ventricular response rates of patients with persistent AF were also noted. The results for ventricular arrhythmias in patients who underwent RSD were similarly poignant, with six of nine studies showing a reduction in ventricular arrhythmias of all kinds following RSD. In the three studies that showed no such effect, the total surveillance time was very low—Ukena [33] had a single 24-h Holter detection period at one follow-up point (6 months post-procedure) whilst McLellan [35] had a 7-day surveillance period at 6 months post-procedure. It is entirely feasible that this is not a long enough surveillance time to detect statistically significant changes in ventricular arrhythmias, especially considering the relative lower frequency of ventricular compared to atrial arrhythmias. The 6-month follow-up point to measure outcomes may initially seem shorter than the 12 months in other studies, though should be long enough to detect changes induced by ventricular remodelling according to the body of the literature in other pathologies where ventricular remodelling is observed such as heart failure. Thus, there seems to be a somewhat conflicting evidential basis for reductions in ventricular arrhythmic burden with RSD. Future studies will have to more carefully define the patient population enrolled into the studies and perhaps concentrate on patient with known IHD and higher burden of ventricular arrhythmias from the outset—this will allow detection of a change in ventricular arrhythmic burden in the patient population that is most at risk and allow studies to detect smaller changes with greater power.

The effect on heart rate is more mixed, with no clear consensus emerging. This may be due to large confounds such as with antiarrhythmic and anti-hypertension medication that may alter heart rate, a whole range of other physiological correlates including co-morbidities as well as the quality of the studies themselves.

There seems to be indications for the efficacy for RSD for blood pressure control with the majority of studies showing statistically lower blood pressure from 6 months onwards in both an ambulatory and office setting. BP control at earlier time points (1–3 months post-RSD) and long-term outcomes of BP control with RSD have not been extensively investigated with only one study investigating outcomes beyond 12 months. The effect of this improved control on pharmacotherapy cannot be determined due to the large variability in reporting in the studies, with in depth dosage and treatment regimens before and after RSD not being available to perform a comparison.

End-organ effects of RSD were explored in terms of both renal and cardiac outcomes. Renal denervation therapy has been used as an invasive but safe procedure to treat heart failure [55]. Importantly, a number of studies reported that RDN improves left ventricular ejection fraction (LVEF), an important prognostic marker and determinant of clinical management. Further echocardiographic measures such as septal wall thickness and ventricular mass indices were also reduced in a number of studies. However, there is conflicting evidence with some studies reporting no such effect. More trials need to be conducted to follow-up on these findings. Similarly, the lack of large and reliable studies was noted as an issue in Fukuta et al. [56], which noted that RSD was associated with a statistically significant increase in LV function (including LVEF) as well as a broader improvement [56]. Similarly, there is conflicting evidence for improvement in eGFR, though reassuringly there is no evidence for RSD being associated with deterioration in renal function even in patients with chronic kidney disease.

Pulmonary vein isolation (PVI) is used widely to treat symptomatic AF; however, its success rate is not optimal and there is a marked recurrence rate of arrhythmia is certain subgroup of patients. However, with the addition of RSD to PVI, the results of several RCTs and meta-analysis seem promising with regards to lowering the rate of AF recurrence significantly [11, 30, 57]. Studies have reported a role for RSD in other atrial and ventricular arrhythmia subtypes, and the majority of studies here demonstrate reduced ventricular arrhythmias. Importantly, however, these studies were not adequately controlled for concomitant antiarrhythmic drug use and a large number of patients were taking beta-blockers in the studies. Further studies are warranted to be able to draw firm conclusions.

In our analysis, it has proven difficult to pool results across studies with regards to the outcomes of RSD largely due to two reasons: (1) the small population size in studies. As RSD has yet to be performed as a standard treatment for arrhythmias, large, randomised studies have not been easy to conduct and the logistically feasible alternatives such as cohort studies in real-world settings have proven useful for investigating different outcomes for RSD. Arrhythmia outcomes in RSD studies often rely on subgroup analysis which are often underpowered with small sample sizes. (2) Large heterogeneity in procedural protocol, treatment regimen, care pathway and RSD equipment. Namely, the majority of studies used RSD in combination with PVI on the treatment arm, and therefore, highlighting the scarcity of evidence of the implications of using RSD in isolation for arrhythmias. Therefore, treatment outcomes across several institutions cannot be compared without acknowledging the fact that the differences mentioned have a role to play in patient outcomes.

This systematic review has several limitations that stem from the quality of studies included. (1) The review included a large number of unblinded, non-randomised observational studies. Data extracted from these cohort studies are potentially affected by biases due to the study design such as selection bias and allocation bias. (2) The generalisability and statistical power of the data is questionable given that the studies mostly do not have a large study population, some as few as 8. (3) The studies were also not powered sufficiently for us to perform subgroup analysis on the outcomes. (4) Most studies include patients with hypertension and form of arrhythmia, i.e. AF. Therefore, it can be argued that the hypothesis drawn based on hypertension patients cannot be extrapolated to patients without hypertension. (5) In some patients, antihypertensives and antiarrhythmic were used alongside RSD, and therefore, could have potentially influenced the true outcome of the procedure. (6) In some studies, the RSD procedure most notably total ablation power delivered, was not standardised and could have an impact on the efficacy of the treatment and outcomes. (7) The patient population in some trials are heterogenous and propensity scores were not matched to minimise confounding factors. (8) The inclusion of several types of arrhythmia as an outcome did not allow us to interpret the outcomes of each arrhythmia individually for a minuscule portion of the analysis. Lastly, the reporting of arrhythmia recurrence was variable which made it difficult for us to pool data and to quantify the difference from various studies for analysis.

To gain a more concrete and directional understanding on the true effects of RSD on cardiac arrhythmias, future studies should be conducted to investigate further the potential clinical efficacy, safety and benefits in arrhythmia patients in large-scale RCTs. These studies should be arrhythmia specific and have long-term outcome measures that go beyond a year post-RSD. The focus of these studies should initially be on AF patients with resistant hypertension as this is currently a major issue in clinical practice. Such studies may produce sufficient data, that might enable the safe, efficacious and minimally invasive RSD to be incorporated into clinical guidelines permitting its use in everyday clinical practice. Consensus on the most effective RSD protocols is also needed, therefore, enabling further research to be done on a multi-centre and international scale. With uniformity in the deliverance of RSD, more direct comparisons could be made, leading to a further therapeutic option in the clinician’s arsenal.

The role of RSD in attenuating AF is becoming more widely accepted when used with PVI [26, 28‐32, 34]. Its potential in treating other arrhythmias has yet to be established but the evidence published till date report promising results.